Treatment of Graves´Ophthalmopathy With Simvastatin (GO-DS)

  • End date
    Mar 30, 2024
  • participants needed
  • sponsor
    Lund University
Updated on 27 February 2022
eye disease
graves' disease


In an investigator initiated multicenter trial (Malm, Odense, rhus) the investigators aim at evaluating activity of Gravesophthalmopathy (GO) and progress to severe GO in patients with mild to moderate Graves ophthalmopathy treated with simvastatin or no treatment.


Progression of GO from mild-moderate to severe disease:

Criteria for start of treatment with corticosteroids, retrobulbar irradiation, or orbital decompression are severe soft tissue swelling (NO SPECS class 2c), risk of corneal ulcers with or without exophthalmos, double vision within 30 degrees, and optic nerve dysfunction. Patients who progress will be followed until the end of the study with the ongoing randomized treatment.

Withdrawal criteria:

  1. Patients may withdraw from the trial at any time without any consequences for their future treatment.
  2. Patients may be withdrawn from the trial at the discretion of the investigator if judged to be non-compliant with trial procedures or due to safety concerns.
  3. Patients must be withdrawn from the trial if they become pregnant or develop congestive heart failure, renal insufficiency, coagulopathy, gastric ulcer, inflammatory bowel disease, diabetic retinopathy, diabetic nephropathy, severe myopathy, or rhabdomyolysis.

Laboratory investigations before randomization:

TSH, fT4, fT3, TRAb, TPOAb, p-glucose, HbA1c, creatinine or cystatin C for estimation of GFR according to the routines of the individual study centers. Biobank samples for analysis of potential markers of ophthalmopathy, DNA (buffy coat), RNA (whole blood), serum, and plasma according to separate sampling instructions.

Clinical appointments and treatment of ophthalmopathy:

Endocrinologist and ophthalmologist judge the presence of ophthalmopathy in patients with Graves disease and asses inclusion and exclusion criteria before randomization to treatment with or without simvastatin.

The activity of ophthalmopathy is judged according to CAS (clinical activity score) and registered by the ophthalmologist:

Spontaneous retrobulbar pain 0. No 1. Yes Painful eye-movements 0. No 1, Yes Eye lid erythema 0. No 1. Yes Conjunctival injection 0. No 1. Yes Chemosis 0. No 1. Yes Swollen caruncula 0. No 1. Yes Eye lid edema or swelling 0. No 1, Yes Sum (points)

In parallel, evaluation with modified CAS is performed and registered by the ophthalmologist:

Spontaneous retrobulbar pain 0. No 1. Mild 2. Moderate 3. Severe Painful eye-movements 0. No

  1. Mild 2. Moderate 3. Severe Eye lid erythema 0. No 1. Mild 2. Moderate 3. Severe Conjunctival injection 0. No 1. Mild 2. Moderate 3. Severe Chemosis 0. No 1. Mild 2. Moderate
  2. Severe Swollen caruncula 0. No 1. Mild 2. Moderate 3. Severe Eye lid edema or swelling 0. No 1. Mild 2. Moderate 3. Severe Sum (points)

Severity is judged by the following parameters and registered in the ophthalmologists protocol: vision, sense of colour, eye papillae edema, eye protrusion, impaired eye movements, corneal ulcers.

Judgement of thyroid function and ophthalmopathy is performed by an endocrinologist/ophthalmologist at inclusion and after 3 and 6 months. The ophthalmologist who evaluates activity and severity of ophthalmopathy is not aware of which treatment arm (simvastatin or control) the patient has been randomized to (single-blind design).

Patients are photographed at each visit and every fifth photograph of ophthalmopathy status is sent to the other centers for evaluation of selected parameters in CAS to evaluate the inter-observer variation.

All patients who fulfill the inclusion criteria and lack exclusion criteria and have signed informed consent will be randomized to treatment simvastatin 40 mg 1x1 or no additional treatment for 6 months. Drugs for treatment are prescribed for 3 months and repeated at control visits. Information on collection of drugs is checked with lists obtained from the pharmacy.

Thyroid treatment:

Patients with Graves hyperthyroidism are treated with ATD. This can be done with the block and replace approach or by titration of ATD according to the local tradition as long as euthyroidism is achieved during the study period (normal fT4 and fT3 with TSH below the upper limit of the local reference interval).

Patients with clinical ophthalmopathy at diagnosis can be included no earlier than 2 months after treatment with ATD and only if biochemical or clinical euthyroidism has been achieved.

Patients who have stopped medication with ATD can be included at the earliest after 2 months and only if clinically and biochemically euthyroid.

Patients who have been treated with radioiodine can be included 6 months after radioiodine if euthyroid. In case of hypothyroidism, patients must be treated with L-thyroxine and be clinically and biochemically euthyroid before inclusion.

Patients who have had thyroidectomy can be included when euthyroidism has been achieved with L-thyroxine.

Statistical considerations and study design:

The primary evaluation variable is change in CAS after 6 months. If it is assumed that the spontaneous change without treatment is -0.6 and if the treatment groups improvement in CAS is -1.9, 34 patients in each group are needed to achieve 80 % power at significance level of 0.05. The basis of this calculation is a study on the effects of selenium treatment in patients with mild to moderate ophthalmopathy (Marcocci 2011).

The investigators will stratify for smoking at randomization which will be performed in blocks of 6 within each participating center.

The secondary exclusion and lost to follow-up rate of patients is estimated to 10 % during the study period. The investigators therefore plan to include a total of 80 patients. The following reasons are expected to cause secondary exclusion/ loss of patients:

  1. Side effects of treatment
  2. Lack of compliance or safety routines not being followed

All patients will receive written information on treatment alternatives, possible side-effects of any drugs used, and the aim of the study which has been approved by relevant ethics committees.

Publication and authorship:

The primary results will be reported in an appropriate medical journal after discussion with the participants of the study and authorship can be claimed if the participant has included at least 10 % of the total number of patients.

Visit schedule:

S = Screening tests, TSH, fT4, fT3, TRAb, TPOAb, Hb, fasting- p-glucose, HbA1c, eGFR (creatinine and cystatin C), ASAT, ALAT, ALP, GT, CK, cholesterol, triglycerides R = Routine tests, TSH, fT4, fT3, Hb, eGFR, CK, ASAT, ALAT, ALP, GT, cholesterol, triglycerides, TRAb, anti-TPO B = Biobank samples according to separate instructions C = Clinical control - vital signs, physical examination, eye status O = Ophthalmologist - eye status, OCT of conjunctive Q = Quality of life questionnaire (SF36,ThyrPro and GO-QoL)

Time 0 S, B, C, O, Q 3 months S, B, C, O, Q 6 months S, B, C, O, Q

Condition Graves Ophthalmopathy, Thyroid Associated Ophthalmopathy, Thyroid Associated Orbitopathy
Treatment simvastatin 40mg, Diclofenac Potassium 50 MG
Clinical Study IdentifierNCT03131726
SponsorLund University
Last Modified on27 February 2022


Yes No Not Sure

Inclusion Criteria

Age 18-70 years
Active mild to moderate with at least one sign of mild GO (NO SPECS class 2a and b) with reference to Colour Atlas at EUGOGO website ([]( Exophthalmos up to 24 mm with a disease duration of <18 months (as recorded by the patient)
Graves disease with clinical and laboratory euthyroidism after stopping treatment with anti thyroid drugs (ATD), or 2 months treatment with ATD, or euthyroid 6 months after treatment with radioiodine, or euthyroid after total thyroidectomy. Clinical and laboratory euthyroidism is defined as normal fT4, fT3 and TSH below the upper limit of the local reference interval and no clinical symptoms or signs of hyperthyroidism. L-thyroxine is used to achieve euthyroidism during the study period

Exclusion Criteria

Pregnancy or breast-feeding
Previous treatment of Graves ophthalmopathy
Severe Graves ophthalmopathy requiring corticosteroid treatment, retrobulbar irradiation, orbital decompression surgery
Current or previous treatment with simvastatin or other statins (within 3 months)
Allergy (skin rash or systemic reactions) to statins
Congestive heart failure
Renal insufficiency (glomerular filtration rate <60 ml/min)
ASAT or ALAT > 2.5 times the upper limit of the local laboratory
Alcoholism as judged by local criteria
Coagulopathy including treatment with warfarin or new oral anti-coagulation drugs
Previous or current gastric ulcer
Inflammatory bowel disease diabetic retinopathy or nephropathy
Trauma within 10 days
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